Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile,Journal of Medicinal Chemistry

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Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-06-17 , DOI: 10.1021/acs.jmedchem.1c00373
Chaowei Ren _{1,

2,

3} , Ning Sun _{1,

4} , Haixia Liu _{1,

3,

5} , Ying Kong ₆ , Renhong Sun _{1,

4} , Xing Qiu ₇ , Jinju Chen ₆ , Yan Li ₆ , Jianshui Zhang ₆ , Yuedong Zhou ₆ , Hui Zhong _{1,

8} , Qianqian Yin ₁ , Xiaoling Song ₁ , Xiaobao Yang ₁ , Biao Jiang _{1,

5,

7}

Affiliation

Proteolysis-targeting chimera (PROTAC) is an attractive technology in drug discovery. Canonically, targets act as a basic starting point in the most previous PROTAC design. Here, we designed degraders considering from the view of clinical benefits. With this novel design, Brigatinib was turned into a degrader SIAIS164018 and endowed with unique features. First, SIAIS164018 could degrade not only ALK fusion proteins in activating or G1202R-mutated form but also mutant EGFR with L858R + T790M, which are two most important targets in non-small-cell lung cancer. Second, SIAIS164018 strongly inhibited cell migration and invasion of Calu-1 and MDA-MB-231. Third and surprisingly, SIAIS164018 degrades several important oncoproteins involved in metastasis such as FAK, PYK2, and PTK6. Interestingly, SIAIS164018 reshuffled the kinome ranking profile when compared to Brigatinib. Finally, SIAIS164018 is orally bioavailable and well tolerated in vivo. SIAIS164018 is an enlightening degrader for us to excavate the charm of protein degradation.

中文翻译：

发现具有破坏转移相关癌蛋白和重组激酶组谱的布加替尼降解剂 SIAIS164018

蛋白水解靶向嵌合体 (PROTAC) 是药物发现中的一项有吸引力的技术。规范地，目标是最早期 PROTAC 设计的基本起点。在这里，我们从临床益处的角度考虑设计了降解剂。通过这种新颖的设计，Brigatinib 变成了一种降解剂 SIAIS164018，并被赋予了独特的功能。首先，SIAIS164018 不仅可以降解激活形式或 G1202R 突变形式的 ALK 融合蛋白，还可以降解具有 L858R + T790M 的突变型 EGFR，这是非小细胞肺癌中两个最重要的靶点。其次，SIAIS164018强烈抑制Calu-1和MDA-MB-231的细胞迁移和侵袭。第三，令人惊讶的是，SIAIS164018 降解了几种与转移有关的重要癌蛋白，例如 FAK、PYK2 和 PTK6。有趣的是，与 Brigatinib 相比，SIAIS164018 重新调整了激酶组排名概况。最后，SIAIS164018 具有口服生物利用度和良好的体内耐受性。SIAIS164018是我们挖掘蛋白质降解魅力的启蒙降解剂。

更新日期：2021-07-08

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